Technical Abstract: To determine the transmissibility of chronic wasting disease (CWD) to cattle and sheep, 13 calves and 8 lambs were inoculated intracerebrally with brain suspension from mule deer (CWD-mule deer) naturally affected with CWD. Both investigations are currently in progress. The cattle experiment was started in 1997. Five and half years post inoculation (PI), 10/13 cattle have either died or were euthanized. Five of these were positive for prion protein (by immunohistochemistry). However, only the initial 2 cattle, euthanized at 23 and 24 months PI, had clinical signs (weight loss), and none revealed obvious histologic changes indicative of spongiform encephalopathy (SE). Three cattle remain alive and apparently healthy. The ovine experiment is 4 years PI and so far 2 sheep (both QQ at codon 171) have been euthanized. Only 1 had clinical signs and histopathologic lesions of SE that were indistinguishable from sheep scrapie, and the brain was positive for prion protein. Six remaining sheep (2 QQ and 4 QR at 171) are apparently healthy. These preliminary findings demonstrate that although the CWD-mule deer agent can be transmitted to cattle and sheep by intracerebral inoculation, an obvious neurologic manifestation of the disease is only seen in the latter species. These results also indicate that the diagnostic techniques currently used for bovine spongiform encephalopathy (BSE) surveillance would also detect the CWD agent in cattle and sheep should it occur naturally. Since intracerebral inoculation is an unnatural route for TSE infection, it has little bearing on the potential for cattle to become infected under natural conditions of exposure and these data may not reflect the situation seen after a natural infection.